Tetrahydropyridoethers

ABSTRACT

The compound (7R,8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1,2-h] [1,7] naphthyridine inhibits the secretion of gastric acid.

This application is a continuation application of U.S. Ser. No.10/783,512, which was filed Feb. 23, 2004 now U.S. Pat. No. 7,105,676,which is a continuation application of U.S. Ser. No. 10/103,733, whichwas filed Mar. 25, 2002, now U.S. Pat. No. 6,696,460, which is acontinuation application of U.S. Ser. No. 09/582,212, which was filedJul. 19, 2000, now U.S. Pat. No. 6,436,953, which was filed under 35U.S.C. 371 as a national stage of PCT/EP99/06899, filed Sep. 17, 1999.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel compounds which are used in thepharmaceutical industry as active compounds for the production ofmedicaments.

KNOWN TECHNICAL BACKGROUND

U.S. Pat. No. 4,468,400 describes tricyclic imidazo[1,2-a]pyridineshaving various ring systems fused onto the imidazopyridine parentstructure, which are said to be suitable for the treatment of pepticulcer disorders.

DESCRIPTION OF THE INVENTION

The invention relates to compounds of the formula I

in whichR1 is methyl or hydroxymethyl,

-   one of the substituents R2a and R2b is hydrogen and the other is    hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or    methoxypropoxy,-   one of the substituents R3a and R3b is hydrogen and the other is    hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or    methoxypropoxy,    where R2a or R2b on the one hand and R3a or R3b on the other hand    are not simultaneously hydroxy, and their salts.

Suitable salts of compounds of the formula I are especially all acidaddition salts. Particular mention may be made of the pharmacologicallytolerable salts of the inorganic and organic acids customarily used inpharmacy. Those suitable are water-soluble and water-insoluble acidaddition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where theacids are employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

Pharmacologically intolerable salts which can be initially obtained asprocess products, for example in the preparation of the compoundsaccording to the invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

The compounds of the formula I have three chiral centers. The inventionrelates to all eight conceivable stereoisomers in any desired mixingratio with one another, including the pure enantiomers, which are apreferred subject of the invention.

A preferred embodiment of the invention are compounds of the formula I*

in whichR1 is methyl or hydroxymethyl,

-   one of the substituents R2a and R2b is hydrogen and the other is    hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or    methoxypropoxy,-   one of the substituents R3a and R3b is hydrogen and the other is    hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or    methoxypropoxy,    where R2a or R2b on the one hand and R3a or R3b on the other hand    are not simultaneously hydroxy, and their salts.

An embodiment (embodiment a) of the invention are compounds of theformula I*,

in which

R1 is methyl,

-   one of the substituents R2a and R2b is hydrogen and the other is    methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,-   one of the substituents R3a and R3b is hydrogen and the other is    hydroxy,    and their salts.

A further embodiment (embodiment b) of the invention are compounds ofthe formula I*,

in which

R1 is methyl,

-   one of the substituents R2a and R2b is hydrogen and the other is    hydroxy,-   one of the substituents R3a and R3b is hydrogen and the other is    methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,    and their salts.

A further embodiment (embodiment c) of the invention are compounds ofthe formula I*,

in which

R1 is methyl,

-   one of the substituents R2a and R2b is hydrogen and the other is    methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,-   one of the substituents R3a and R3b is hydrogen and the other is    methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,    and their salts.

A further embodiment (embodiment d) of the invention are compounds ofthe formula I*,

in which

R1 is hydroxymethyl,

-   one of the substituents R2a and R2b is hydrogen and the other is    methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,-   one of the substituents R3a and R3b is hydrogen and the other is    hydroxy,    and their salts.

A further embodiment (embodiment e) of the invention are compounds ofthe formula I*,

in which

R1 is hydroxymethyl,

-   one of the substituents R2a and R2b is hydrogen and the other is    hydroxy,-   one of the substituents R3a and R3b is hydrogen and the other is    methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,    and their salts.

A further embodiment (embodiment f) of the invention are compounds ofthe formula I*,

in which

R1 is hydroxymethyl,

-   one of the substituents R2a and R2b is hydrogen and the other is    methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,-   one of the substituents R3a and R3b is hydrogen and the other is    methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,    and their salts.

Preferred compounds of the embodiments a to f are those, in which R3b ishydrogen.

Particularly preferred compounds of the embodiments a to f are those, inwhich R2a and R3b are hydrogen.

Preferred compounds within the scope of the invention are those ofembodiment a, which can be characterized by the formula I**

in whichone of the substituents Ra and Rb is hydrogen and the other is methoxy,ethoxy, isopropoxy, methoxyethoxy or methoxypropoxyand their salts.

Particularly preferred compounds of embodiment a are those of formulaI**, in which

Ra is hydrogen and

Rb is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy,

an their salts.

With the aid of the general formula I*, the following exemplarypreferred compounds according to the invention may actually be mentionedby means of the substituent meanings for R1, R2a, R2b, R3a and R3b inthe following Table 1 (Tab. 1):

TABLE 1 R1 R2a R2b R3a R3b CH₃ H OCH₃ OH H CH₃ H OC₂H₅ OH H CH₃ HOCH(CH₃)₂ OH H CH₃ H OCH₂CH₂OCH₃ OH H CH₃ H OCH₂CH₂CH₂OCH₃ OH H CH₃ H OHOCH₃ H CH₃ H OH OC₂H₅ H CH₃ H OH OCH(CH₃)₂ H CH₃ H OH OCH₂CH₂OCH₃ H CH₃H OH OCH₂CH₂CH₂OCH₃ H CH₃ H OCH₃ OCH₃ H CH₃ H OC₂H₅ OC₂H₅ H CH₃ HOCH(CH₃)₂ OCH(CH₃)₂ H CH₃ H OCH₂CH₂OCH₃ OCH₂CH₂OCH₃ H CH₃ HOCH₂CH₂CH₂OCH₃ OCH₂CH₂CH₂OCH₃ H CH₂OH H OCH₃ OH H CH₂OH H OC₂H₅ OH HCH₂OH H OCH(CH₃)₂ OH H CH₂OH H OCH₂CH₂OCH₃ OH H CH₂OH H OCH₂CH₂CH₂OCH₃OH H CH₂OH H OH OCH₃ H CH₂OH H OH OC₂H₅ H CH₂OH H OH OCH(CH₃)₂ H CH₂OH HOH OCH₂CH₂OCH₃ H CH₂OH H OH OCH₂CH₂CH₂OCH₃ H CH₂OH H OCH₃ OCH₃ H CH₂OH HOC₂H₅ OC₂H₅ H CH₂OH H OCH(CH₃)₂ OCH(CH₃)₂ H CH₂OH H OCH₂CH₂OCH₃OCH₂CH₂OCH₃ H CH₂OH H OCH₂CH₂CH₂OCH₃ OCH₂CH₂CH₂OCH₃ H CH₃ OCH₃ H OH HCH₃ OC₂H₅ H OH H CH₃ OCH(CH₃)₂ H OH H CH₃ OCH₂CH₂OCH₃ H OH H CH₃OCH₂CH₂CH₂OCH₃ H OH H CH₃ OH H OCH₃ H CH₃ OH H OC₂H₅ H CH₃ OH HOCH(CH₃)₂ H CH₃ OH H OCH₂CH₂OCH₃ H CH₃ OH H OCH₂CH₂CH₂OCH₃ H CH₃ OCH₃ HOCH₃ H CH₃ OC₂H₅ H OC₂H₅ H CH₃ OCH(CH₃)₂ H OCH(CH₃)₂ H CH₃ OCH₂CH₂OCH₃ HOCH₂CH₂OCH₃ H CH₃ OCH₂CH₂CH₂OCH₃ H OCH₂CH₂CH₂OCH₃ H CH₂OH OCH₃ H OH HCH₂OH OC₂H₅ H OH H CH₂OH OCH(CH₃)₂ H OH H CH₂OH OCH₂CH₂OCH₃ H OH H CH₂OHOCH₂CH₂CH₂OCH₃ H OH H CH₂OH OH H OCH₃ H CH₂OH OH H OC₂H₅ H CH₂OH OH HOCH(CH₃)₂ H CH₂OH OH H OCH₂CH₂OCH₃ H CH₂OH OH H OCH₂CH₂CH₂OCH₃ H CH₂OHOCH₃ H OCH₃ H CH₂OH OC₂H₅ H OC₂H₅ H CH₂OH OCH(CH₃)₂ H OCH(CH₃)₂ H CH₂OHOCH₂CH₂OCH₃ H OCH₂CH₂OCH₃ H CH₂OH OCH₂CH₂CH₂OCH₃ H OCH₂CH₂CH₂OCH₃ H Andthe salts of these compounds.

The compounds according to the invention can be prepared as described byway of example in the following examples, or using analogous processsteps starting from appropriate starting compounds (see, for example,EP-A-0 299 470 or Kaminski et al., J. Med. Chem. 1985, 28, 876-892). Thestarting compounds are known or can be prepared analogously to the knowncompounds. The compounds according to the invention can be prepared forexample starting from N-protected 8-amino-imidazo[1,2-a]pyridinesaccording to the following reaction scheme:

The above scheme represents an example of an enantioselective synthesis.The N-protected (Piv represents a customary protective group, preferablythe pivaloyl group), 8-aminoimidazo[1,2-a]pyridine deprotonated in the7-position is reacted with an enantiomerically pure dioxolane. Thisinitially leads to a condensation product which can be cyclized understrongly acidic conditions with removal of the protecting groups. Thesubsequent reduction of the keto group using sodium borohydride leads inover 90% enantiomeric purity to the 7,8-trans-diol indicated. Thesubsequent etherification which is carried out according to knownprocesses, e.g. as described in the Examples, leads to the finalproducts of formula I* in which R2a and R3b are hydrogen. Thecorresponding 7,8-cis-compound is obtained from the mother liquor, whichis left after separating off the 7,8-trans-compound, by chromatographicpurification.

The substances according to the invention are isolated and purified in amanner known per se, for example, by distilling off the solvent in vacuoand recrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such as, forexample, column chromatography on suitable support material.

Salts are obtained by dissolving the free compound in a suitablesolvent, e.g. in a chlorinated hydrocarbon, such as dichloromethane orchloroform, or a low molecular weight aliphatic alcohol (ethanol,isopropanol) which contains the desired acid, or to which the desiredacid is subsequently added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted byalkalization or by acidification into the free compounds, which in turncan be converted into salts. In this way, pharmacologically intolerablesalts can be converted into pharmacologically tolerable salts.

The pure enantiomers, in particular the pure enantiomers of the formulaI*, to which the invention preferably relates, can be obtained in amanner familiar to the person skilled in the art, for example byenantioselective synthesis (see, for example, the Scheme), bychromatographic separation on chiral separating columns, byderivatization with chiral auxiliary reagents, subsequent separation ofdiastereomers and removal of the chiral auxiliary group, by saltformation with chiral acids, subsequent separation of the salts andliberation of the desired compound from the salt, or by (fractional)crystallization from a suitable solvent. Trans-products obtained (withR2a and R3b=hydrogen) can be converted (at least partly) to thecorresponding cis-products (with R2b and R3b=hydrogen) by standing underacidic conditions (e.g. 2 equivalents of acid, such as sulfuric acid) inthe corresponding alcohol R2a-OH. Likewise, cis-products obtained can beconverted to the corresponding trans-products. The cis- andtrans-products are separated e.g. by chromatography or bycrystallization.

The following examples serve to illustrate the invention further withoutrestricting it. Likewise, further compounds of the formula I whosepreparation is not described explicitly can be prepared analogously orin a manner familiar to the person skilled in the art using customaryprocess techniques. The abbreviation min stands for minute(s), h forhour(s) and ee for enantiomeric excess.

EXAMPLES Final Products 1A.(7R,8R,9R)-2,3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

Method a

20 g (65 mmol) of(7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridineare dissolved in methanol (350 ml). 13.5 g of sulfuric acid are addedand the solution is stirred for 48 h at 50° C. After cooling thereaction mixture is poured into 250 ml of water. The pH is adjusted byaqueous saturated sodium hydrogen carbonate solution to neutral pH. Theprecipitate is collected and purified on silica gel (eluent:diethylether). 2.5 g of the title compound are obtained as colourlesscrystals of melting point 164-165° C. (2-propanol).

Method b

10 g (32.5 mmol) of(7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridineare dissolved in 200 ml of dry dimethylformamide. 1.9 g of commerciallyavailable sodium hydride in paraffin (80%) are added in small portionsat room temperature. After 1 h 9.1 g (65 mmol) of methyl iodide,dissolved in 4 ml of dimethylformamide, are added and the mixture isstirred for an additional hour. The reaction mixture is poured into coldwater. 20 ml of a saturated aqueous ammonium chloride solution is added,the yellow precipitate is collected and discarded. The filtrate isextracted several times with ethyl acetate, the combined organic phasesare washed several times with water and the solvent is evaporated invacuo. The solid residue is purified on silica gel (diethylether). 2 gof the title compound are obtained as colourless crystals of meltingpoint 164-165° C. (2-propanol).

1B.(7S,8S,9S)-2,3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

The title compound of melting point 161-162° C. is obtained similarly tothe procedure described in Example 1, Method a, using(7S,8S,9S)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]naphthyridineas starting material.

2A. (7S,8R,9R)-2,3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

6 g of the title compound are obtained as colourless powder of meltingpoint 108-110° C. after purification on silica gel according to Example1A, Method a, starting from(7S,8R,9R)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine.

2B.(7R,8S,9S)-2,3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

The title compound of melting point 171-172° C. is obtained from themother liquor of Example 1B after purification on silica gel (eluent:diethyl ether).

3.(7R,8R,9R)-2,3-Dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

500 mg of the title compound are obtained by reaction of(7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridinewith ethanol and sulfuric acid according to Example 1, Method a, afterpurification on silica gel (eluent: diethylether). Melting point:188-190° C.

4.(7S,8R,9R)-2,3-Dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-[1,7]naphthyridine

800 mg of the title compound of melting point 135-137° C. are obtainedas a solid by further purification of the mother liquor of Example 3 onsilica gel.

5A.(7R,8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imi-dazo[1,2-h][1,7]naphthyridine

Method a

5 g of the title compound of melting point 130-1° C. are obtained byreaction of 20 g(7R,8R,9R)-2,3-di-methyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridinewith 2-methoxy-ethanol according to Example 1, Method a.

Method b

To a solution of 100 g of(7R,8R,9R)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2h][1,7]naphthyridinein 11 of 2-ethoxyethanol, 64 g of concentrated sulfuric acid are addedslowly at room temperature under an argon atmosphere. The rate ofaddition is such that the temperature of the mixture does not exceed 35°C. After further 15 hours of stirring at room temperature the greenishsolution is poured into a mixture of 1 kg of crushed ice and 800 ml ofdichloromethane. The pH of the stirred mixture is adjusted to 7.5 byaddition of a 10 M aqueous sodium hydroxide solution, the organic layeris separated off, the aqueous layer is extracted three times withdichloromethane (200 ml each), the dichloromethane layers are washedcollectively with 500 ml of water (six times) and are then dried oversodium sulfate. After complete evaporation of the solvent under reducedpressure the remaining oily residue is treated with 450 ml of acetone toyield 75 g off-white crystals consisting of a 1:1 mixture of the titlecompound and its (7S,8R,9R)-epimer. The mixture is separated bypreparative HPLC using methanol as eluent. 28 g of the title compound ofmelting point 128°-129° C. are obtained after recrystallization fromethyl acetate.

5B.(7S,8S,9S)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imi-dazo[1,2-h][1,7]naphthyridine

The title compound of melting point 130°-131° C. is obtained similarlyto the procedure described in Example 5A, Method a, using (7S, 8S,9S)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]naphthyridineas starting material.

6A.(7S,8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imi-dazo[1,2-h][1,7]naphthyridine

7.8 g of the title compound of melting point 131-132° C. are obtained asa solid from the mother liquor of Example 5A after purification onsilica gel (eluent: diethyl ether).

6B.(7R,8S,9S)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imi-dazo[1,2-h][1,7]naphthyridine

The title compound of melting point 131°-132° C. is obtained from themother liquor of Example 5B after purification on silica gel (eluent:diethyl ether).

7.(7S,8R,9R)-2,3-Dimethyl-8-hydroxy-9-phenyl-7-(2-propoxy)-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

1 g of the title compound of melting point 168-9° C. is obtained byreaction of 3 g of(7R,8R,9R)-2,3-di-methyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridinewith 2-propanol according to Example 1, Method a.

8.(7R,8R,9R)-2,3-Dimethyl-7,8-dimethoxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

8 g of the title compound of melting point 155-156° C. are obtained byreaction of 10 g of(7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridinewith 1,9 g of sodium hydride (80%) and 9,1 g of methyl iodide accordingto Example 1, Method b.

Starting compounds A1.2,3-Dimethyl-7-[(2R,3S)-2,3-O-isopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylamino-imidazo[1,2-a]pyridine

60 g (0.245 mol) of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridineare dissolved in 1.5 l of anhydrous diethyl ether with exclusion ofmoisture and under an argon atmosphere and cooled to −75° C. By means ofa flex needle, 408 ml (0.612 mol) of tert-butyllithium solution (1.5 Min n-pentane) are added dropwise such that the temperature does notexceed −65° C. (30 min). A red suspension is formed. After addition iscomplete, the suspension is stirred at −75° C. for further 30 min. ⅓ ofa solution of 145 g of methyl(2R,3S)-2,3-O-isopropylidene-3-phenylpropionate (ee: 99.05%, DaicelChiralcel HPLC) in 150 ml of dry THF is then slowly added dropwise at atemperature below −65° C. during the course of 30 min. The residualquantity is then briskly added (5 min), a temperature rise to −60° C.taking place. After addition is complete the cooling bath is removed. Onreaching an internal temperature of −30° C., 20 ml of methanol are addedand at an internal temperature of 0° C. 200 ml of distilled water areadded. The aqueous phase is separated off in a separating funnel, theorganic phase is washed five times with 100 ml of distilled water eachtime, then the organic phase is extracted three times with 10% strengthsulfuric acid (200 ml, 50 ml, 50 ml). The sulfuric acid phases arecombined, treated with 200 ml of dichloromethane and adjusted to pH 2.3with 10N sodium hydroxide solution and with ice cooling and vigorousstirring. The organic layer is separated off. The aqueous phase isextracted with 30 ml of dichloromethane. The combined dichloromethanephases are washed twice with a little distilled water. The organic layeris then dried over anhydrous sodium sulfate and the solvent iscompletely stripped off in vacuo. A brown oil is obtained which istreated with 50 ml of diethyl ether. After seeding, crystals are formedwhich are filtered off after standing overnight and washed with diethylether. After drying in vacuo, 57.7 g (52.5%, ee>99%, Daicel ChiralcelHPLC) of the title compound of melting point 76-80° C. are obtained as apale yellow powder.

A2.2,3-Dimethyl-7-[(2S,3R)-2,3-O-isopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylamino-imidazo[1,2-a]pyridine

The title compound (ee: 98.3%, Daicel Chiralcel HPLC) is obtainedsimilarly to the procedure described in example A1 by using methyl(2S,3R)-2,3-O-isopropylidene-3-phenylpropionate (ee: 98%, DaicelChiralcel HPLC) as acylating agent.

B1.(8R,9R)-2,3-Dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one

10.8 g (24 mmol) of2,3-dimethyl-7-[(2R,3S)-2,3-O-isopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylaminoimidazo[1,2-a]pyridine(ee>95%, Daicel Chiralcel HPLC) are introduced into 50 ml of 70%strength sulfuric acid with ice cooling during the course of 4 min. Asuspension is formed in the course of this, which turns into an orangesolution after 30 min. After addition is complete, the ice bath isremoved and the mixture is stirred on at room temperature. The reactionsolution is added after 50 h to ice water and dichloromethane is added,then the mixture is adjusted to pH 8 using 6N sodium hydroxide solutionand saturated sodium hydrogen-carbonate solution. The organic phase isseparated off. The aqueous phase is extracted twice withdichloromethane. The organic phases are combined and washed with alittle distilled water. The organic layer is then dried over anhydroussodium sulfate, filtered and concentrated on a vacuum rotary evaporator.The concentrated residue is chromatographed on silica gel (eluent:dichloromethane/methanol 100/1). The main fraction is concentrated andtreated with ethyl acetate, and the title compound crystallizes in thecourse of this as a yellow solid. This precipitate is filtered off withsuction and dried to constant weight in a vacuum drying oven at 50° C.4.22 g (57%, ee>95%, Daicel Chiralcel HPLC) of the title compound ofmelting point 231-4° C. are obtained.

B2.(8S,9S)-2,3-Dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one

The title compound (ee: 94.0%, Daicel Chiralcel HPLC) is obtainedaccording to the procedure described in example B1 starting from2,3-dimethyl-7-[(2S,3R)-2,3-O-isopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylaminoimidazo[1,2-a]pyridine.

C1.(7R,8R,9R)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]-naphthyridine

6 g (19.52 mmol) of(8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetra-hydroimidazo-[1,2-h][1,7]naphthyridin-7-one(ee>90%, Daicel Chiralcel HPLC) are suspended in 60 ml of methanol andcooled to −5° to 0° C. in a methanol-ice bath. At this temperature,sodium borohydride (0.81 g, 21.47 mmol) is added by spatula during thecourse of 0.5 h (evolution of gas). After addition is complete, themixture is stirred for a further 10 min, and then concentrated in avacuum rotary evaporator at a bath temperature of 40° C. The oilyresidue obtained is taken up in distilled water and extracted threetimes with chloroform. The organic phases are combined and washed with alittle water, then dried using anhydrous sodium sulfate and filtered.The filtrate is concentrated on a vacuum rotary evaporator andco-evaporated with acetone; the title compound crystallizes out in thecourse of this. The precipitate is filtered off, washed with acetone anddried to constant weight at 50° C. in a vacuum drying oven. 5.15 g(85.3%, ee>90%, Daicel Chiralcel HPLC) of the title compound areobtained as a colorless crystallizate of melting point 206-9° C.

C2.(7S,8S,9S)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]naphthyridine

The title compound of mp 207-208° C. (ee: 98.7%, Daicel Chiralcel HPLC)is obtained according to the procedure described in example C1 using(8S,9S)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-oneas starting material.

D.(7S,8R,9R)-2,3-Dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

2 g of the mother liquor of Example C1 are chromatographed on silica gel(eluent: ethyl acetate/methanol 19/1) to give 0.35 g of the titlecompound as an oil which crystallizes upon addition of ethyl acetate.Melting point.: 199-200° C. (ethyl acetate).

Commercial Utility

The compounds of the formula I and their salts have usefulpharmacological properties which make them commercially utilizable. Inparticular, they exhibit a marked inhibition of gastric acid secretionand an excellent gastric and intestinal protective action inwarm-blooded animals, in particular humans. In this context, thecompounds according to the invention are distinguished by a highselectivity of action, an advantageous duration of action, aparticularly good enteral activity, the absence of significant sideeffects and a large therapeutic breadth.

“Gastric and intestinal protection” in this connection is understood asmeaning the prevention and treatment of gastrointestinal diseases, inparticular of gastrointestinal inflammatory diseases and lesions (suchas, for example, stomach ulcers, duodenal ulcers, gastritis, hyperacidicor medicament-related functional gastropathy), which can be caused, forexample, by microorganisms (e.g. Helicobacter pylori), bacterial toxins,medicaments (e.g. certain antiinflammatories and antirheumatics),chemicals (e.g. ethanol), gastric acid or stress situations.

In their excellent properties, the compounds according to the inventionsurprisingly prove to be clearly superior to the compounds known fromthe prior art in various models in which the antiulcerogenic and theantisecretory properties are determined. On account of these properties,the compounds of the formula I and their pharmacologically tolerablesalts are outstandingly suitable for use in human and veterinarymedicine, where they are used, in particular, for the treatment and/orprophylaxis of disorders of the stomach and/or intestine.

The invention therefore further relates to the compounds according tothe invention for use in the treatment and/or prophylaxis of theabovementioned diseases.

The invention likewise comprises the use of the compounds according tothe invention for the production of medicaments which are employed forthe treatment and/or prophylaxis of the abovementioned diseases.

The invention furthermore comprises the use of the compounds accordingto the invention for the treatment and/or prophylaxis of theabovementioned diseases.

The invention furthermore relates to medicaments which contain one ormore compounds of the formula I and/or their pharmacologically tolerablesalts.

The medicaments are prepared by processes known per se, which arefamiliar to the person skilled in the art. As medicaments, thepharmacologically active compounds according to the invention (=activecompounds) are employed either as such, or preferably in combinationwith suitable pharmaceutical auxiliaries or excipients in the form oftablets, coated tablets, capsules, suppositories, patches (e.g. as TTS),emulsions, suspensions or solutions, where the active compound contentis advantageously between 0.1 and 95% and where, by the appropriatechoice of the auxiliaries and excipients, a pharmaceuticaladministration form (e.g. a delayed-release form or an enteric form)exactly suited to the active compound and/or to the desired onset ofaction can be achieved.

The person skilled in the art is familiar, on the basis of his expertknowledge, with auxiliaries or excipients which are suitable for thedesired pharmaceutical formulations. Beside solvents, gel-formingagents, suppository bases, tablet auxiliaries and other active compoundcarriers, it is possible to use, for example, antioxidants, dispersants,emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers,colorants or, in particular, permeation promoters and complexing agents(e.g. cyclodextrins).

The active compounds can be administered orally, parenterally orpercutaneously.

In general, it has proven advantageous in human medicine to administerthe active compound(s) in the case of oral administration in a dailydose from approximately 0.01 to approximately 20, preferably 0.05 to 5,in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in theform of several, preferably 1 to 4, individual doses to achieve thedesired result. In the case of parenteral treatment, similar or (inparticular in the case of intravenous administration of the activecompounds), as a rule, lower doses can be used. The optimal dose andmanner of administration of the active compounds necessary in each casecan easily be determined by any person skilled in the art on the basisof his expert knowledge.

If the compounds according to the invention and/or their salts are to beemployed for the treatment of the abovementioned diseases, thepharmaceutical preparations can also contain one or morepharmacologically active constituents of other pharmaceutical groups.Examples which may be mentioned are: tranquilizers (for example from thebenzodiazapines group, e.g. diazepam), spasmolytics (e.g. bietamiverineor camylofin), anticholinergics (e.g. oxyphencyclimine orphencarbamide), local anesthetics (e.g. tetracaine or procaine), and, ifappropriate, also enzymes, vitamins or amino acids.

To be emphasized in this connection, in particular, is the combinationof the compounds according to the invention with pharmaceuticals whichinhibit acid secretion, such as, for example, H2 blockers (e.g.cimetidine, ranitidine), H+/K+− ATPase inhibitors (e.g. omeprazole,pantoprazole), or furthermore with so-called peripheral anticholinergics(e.g. pirenzepine, telenzepine), and with gastrin antagonists with theaim of increasing the main action in an additive or superadditive senseand/or of eliminating or decreasing the side effects, or furthermore thecombination with antibacterially active substances (e.g. cephalosporins,tetracyclines, penicillins, macrolides, nitroimidazoles or alternativelybismuth salts) for the control of Helicobacter pylori. Antibacteriallyactive combination components which may be mentioned are, for example,mezlocillin, ampicillin, amoxycillin, cefalothin, cefoxitin, cefotaxime,imipenem, gentamycin, amikacin, erythromycin, ciprofloxacin,metronidazole, clarithromycin, azithromycin and combinations thereof(e.g. clarithromycin+metronidazole).

Pharmacology

The excellent gastric protective action and the gastric acidsecretion-inhibiting action of the compounds according to the inventioncan be demonstrated in animal experimental models. The compoundsaccording to the invention investigated in the model mentioned belowhave been provided with numbers which correspond to the numbers of thesecompounds in the examples.

Testing of the Secretion-Inhibiting Action on the Perfused Rat Stomach

Table A below shows the effects of the compounds according to theinvention on the pentagastrin-stimulated acid secretion of the perfusedrat stomach in vivo after intravenous administration.

TABLE A Dose Inhibition of acid (μmol/kg) secretion No. i.v. (%) 1 3 1002 3 100 3 3 100 4 3 100 5 3 100 6 3 100 7 3 100 8 3 100Methodology

The abdomen of anesthetized rats (CD rat, female, 200-250 g; 1.5 g/kgi.m. urethane) was opened after tracheotomy by means of a median upperabdominal incision and a PVC catheter was fixed transorally in theesophagus and another via the pylorus such that the ends of the tubejust projected into the gastric lumen. The catheter leading from thepylorus led outwards into the right abdominal wall through a sideopening.

After thorough rinsing (about 50-100 ml), warm physiological NaClsolution at 37° C. was continuously passed through the stomach (0.5ml/min, pH 6.8-6.9; Braun-Unita I). The pH (pH meter 632, glasselectrode EA 147; φ=5 mm, Metrohm) and, by titration with a freshlyprepared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm), thesecreted HCl were determined in the effluent in each case collected atan interval of 15 minutes.

The gastric secretion was stimulated by continuous infusion of 1 μg/kg(=1.65 ml/h) of i.v. pentagastrin (left femoral vein) about 30 min afterthe end of the operation (i.e. after determination of 2 preliminaryfractions). The substances to be tested were administered intravenouslyin 1 ml/kg liquid volumes 60 min after the start of the pentagastrincontinuous infusion.

The body temperature of the animals was kept at a constant 37.8-38° C.by infrared irradiation and heat pads (automatic, stepless control bymeans of a rectal temperature sensor).

1. The compound(7R,8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1,2-h][1,7]naphthyridine or a pharmaceutically acceptable salt thereof.
 2. Apharmaceutical composition comprising the compound(7R,8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine or a pharmaceutically acceptable salt thereof, togetherwith a pharmaceutically acceptable auxiliary or excipient.
 3. A methodof inhibiting acid secretion in a patient comprising administering to apatient in need thereof, the compound(7R,8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1,2-h][1,7]naphthyridine or a pharmaceutically acceptable salt thereof.